Scientists Map Changes in Genetic Networks Caused by DNA Damage

The research is significant because it represents a major technological leap forward from simply compiling lists of genes in an organism to actually describing how these genes actively work together.

"Cell behaviour is dynamic, but the genetic networks that govern these behaviours have been studied mostly only under normal, benign laboratory conditions," said Doctor Trey Ideker, UCSD School of Medicine. "This work is the next milestone. It shows that we can map how genetic networks in cells are reprogrammed in response to stimuli, thus revealing functional relationships that would go undetected using other approaches."

Think of it as the difference in the informational value of a photograph versus a video. In the photo, details and data are restricted to what is contained in a single, captured moment. There is no way to determine exactly what occurred before or after, or how players in the picture changed. In a video, on the other hand, whole sequences of events– dynamic processes and responses, interactions and relationships – can be chronicled, identified and studied.

Epistasis refers to the interaction of genes and how they suppress, amplify or alter each other's functions. To create a differential epistasis map, the researchers focused on 400 or so genes that govern the signalling pathways in a yeast cell. They then created 80,000 double-mutant cell lines in which each line carried mutations in a different pair of the 400 genes. When double-mutant cells grow much more slowly or quickly than expected, these mutant genes are said to interact.

To create the differential map, interactions were identified both before and after exposure to a DNA-damaging compound similar to drugs used in chemotherapy. These two networks were then subtracted, one from the other, to reveal differences. Remarkably, researchers found that most of the interactions identified with the drug were not present without it, and vice versa. In other words, the genetic network was completely reprogrammed by DNA damage.

As researchers progress in mapping these networks, their dynamic nature is both enlightening and depressing, said Ideker. Scientists had hoped cellular networks might not change greatly across different conditions or from cell to cell. That they do so suggests greater challenges and complexities ahead.